Abstract
Overlap syndromes of long QT 3 syndrome (LQT3) and the Brugada syndrome (BrS) have been reported. Identification of patients with an overlapping phenotype is crucial before initiation of Class I antiarrhythmic drugs for LQT3. Aim of the present study was to elucidate the yield of ajmaline challenge in unmasking the Brugada phenotype in patients with LQT3 caused by the most common mutation, SCN5A-E1784K.
Consecutive families in tertiary referral centres diagnosed with LQT3 caused by SCN5A-E1784K were included in the study. Besides routine clinical work-up, ajmaline challenge was performed after informed consent. A total of 23 subjects (11 female, mean age 27 ± 14 years) from 4 unrelated families with a family history of sudden cardiac death and familial diagnosis of the SCN5A-E1784K mutation underwent ajmaline challenge and genetic testing. Sixteen subjects (9 female) were found to be heterozygous carriers of SCN5A-E1784K. Ajmaline challenge was positive in 12 out of the 16 (75%) mutation carriers, but negative in all non-carriers. Following ajmaline, a significant shortening of the rate-corrected JT (JTc) interval was observed in mutation carriers. The baseline JTc interval was significantly longer in mutation carriers with a positive ajmaline challenge compared with those with a negative one.
Overlap of LQT3 and BrS in patients carrying the most common mutation is high. Therefore, ajmaline challenge represents an important step to rule out potential BrS overlap in these patients before starting sodium channel blockers for the beneficial effect of QT shortening in LQT3.
Overlap with the Brugada phenotype in carriers of the most prevalent long QT 3 causing mutation, SCN5A-E1784K, is high.
SCN5A-E1784K mutation carriers with a negative ajmaline challenge seem to exhibit a less severe electrocardiographic long QT phenotype.
Ajmaline challenge was well tolerated in carriers of SCN5A-E1784K.
Introduction
Long QT syndrome (LQTS) and the Brugada syndrome (BrS) are inheritable diseases predisposing to cardiac arrhythmias and sudden death in patients with structurally normal hearts. Distinct mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for long QT 3 syndrome (LQT3), BrS, cardiac conduction disease, and sick sinus syndrome. Some of these mutations, such as SCN5A-1795insD, SCN5A-ΔK1500, or SCN5A-D1790G, have been shown to cause an overlapping phenotype.1–3
Being the most prevalent LQT3 causing mutation, SCN5A-E1784K accounts for more than 10% of genotyped unrelated LQT3 patients.4 This mutation, initially described as LQTS causing,5 has also been associated with an overlap phenotype of LQTS, BrS, cardiac conduction disease, and sick sinus syndrome in some patients.6 The use of Class I antiarrhythmic drugs has been proposed in LQT3 in order to shorten the QT interval and reduce arrhythmia burden, but the use of sodium channel blocking drugs should be avoided in BrS.7 Thus, identification of patients with an additional Brugada phenotype is crucial before initiation of Class I antiarrhythmic drugs in LQT3. Sodium channel blocker challenge using ajmaline has been identified as more sensitive than flecainide for unmasking the Brugada phenotype.8
Aim of the present study was to elucidate the yield of ajmaline challenge in unmasking the Brugada phenotype in patients with LQT3 caused by the most common mutation, SCN5A-E1784K.
Methods
Study population
Consecutive families diagnosed with LQT3 caused by SCN5A-E1784K in three tertiary referral centres were included in the study. All patients underwent routine clinical work-up including medical history, clinical examination, 12-lead electrocardiogram (ECG), stress test, and echocardiogram. Additionally, ajmaline challenge was performed as part of the clinical work-up. Further examinations and treatment were left to the treating physician's discretion. All patients gave informed consent to the study. The study was approved by the institutional committees on human research at the authors' institutions.
Sodium channel blocker challenge
In all patients, intravenously administered ajmaline was used for sodium channel blocker challenge according to current guidelines.7 The detailed protocol has been described earlier.9 In short, ajmaline was administered up to a maximum dose of 1 mg/kg body weight within 5 min under continuous 12-lead ECG monitoring. Modified right precordial leads were positioned in the second and third intercostal spaces in right para-sternal, mid-sternal, and left para-sternal positions.10 Ajmaline administration was discontinued, and the test considered positive when a diagnostic type I ECG pattern7 appeared in at least one right precordial lead. Further criteria for discontinuing the challenge were the occurrence of PVCs or VT, prolongation of the QRS duration >130%, or the occurrence of higher-degree AV block.
Electrocardiogram analysis
All ECGs were digitized. Measurements were performed using a digital calliper in Acrobat Professional 8.0 (Adobe, Inc., San Jose, CA, USA). The rate-corrected QT (QTc) interval was calculated using the Bazett formula, QTc = QT/√(preceding RR). Several rate correction formulas for JT have been proposed of which Hodges' linear formula shows the least residual rate dependence in structurally normal hearts.11 We therefore report both the analogue of the Bazett formula, JTc1 = JT/√(preceding RR), and Hodges' formula, JTc2 = JT + 1.75 × (heart rate−60), to correct for differences in heart rate during ajmaline challenge.
The J point elevation was measured at the end of the QRS complex in conventional and modified right precordial leads. The maximum J point elevation in any of these leads is reported.
Ajmaline challenges were rated as positive (type 1 Brugada pattern) or negative according to current guidelines7 by two electrophysiologists blinded to mutation status.
Statistics
Data are reported as mean ± standard deviation. Continuous variables were compared using the two-sided paired or unpaired Student's t-test. Homogeneity of variance was tested using Levene's test with P < 0.1 considered heterogeneous. χ2 test and Fisher's exact test were used for comparison of categorical variables. A P-value of <0.05 was considered statistically significant. All calculations were performed using SPSS 23 (SPSS, Inc., Chicago, IL, USA).
Results
Demographic and clinical data
A total of 23 subjects (11 female, mean age 27 ± 14 years) from 4 unrelated families underwent ajmaline challenge and genetic testing because of a family history of sudden cardiac arrest and familial diagnosis of an SCN5A-E1784K mutation. No patient was on antiarrhythmic drugs at the time of the ajmaline challenge. Sixteen subjects (9 female) were found to be heterozygous carriers of SCN5A-E1784K; in the remaining 7 family members (2 female), the mutation was not found. Mean age at ajmaline challenge was 26 years (range 13–54 years) in mutation carriers and 30 years (range 11–56 years) in mutation negative subjects (P = 0.55). Patient characteristics are shown in Table 1.
Patient characteristics
| SCN5A-E1784K positive | SCN5A-E1784K negative | Total | |
|---|---|---|---|
| n | 16 | 7 | 23 |
| Female | 9 (56%) | 2 (29%) | 11 (48%) |
| Age at ajmaline challenge (years) | 26.0 ± 13.9 | 30.0 ± 15.9 | 27.2 ± 14.3 |
| Family history of SCD/SCA in first-degree relative | 6 (38%) | 3 (43%) | 9 (39%) |
| Symptoms (SCA or syncope) | 2 (13%) | 0 | 2 (9%) |
| ICD implanted | 8 (50%) | 0 | 8 (35%) |
| SCN5A-E1784K positive | SCN5A-E1784K negative | Total | |
|---|---|---|---|
| n | 16 | 7 | 23 |
| Female | 9 (56%) | 2 (29%) | 11 (48%) |
| Age at ajmaline challenge (years) | 26.0 ± 13.9 | 30.0 ± 15.9 | 27.2 ± 14.3 |
| Family history of SCD/SCA in first-degree relative | 6 (38%) | 3 (43%) | 9 (39%) |
| Symptoms (SCA or syncope) | 2 (13%) | 0 | 2 (9%) |
| ICD implanted | 8 (50%) | 0 | 8 (35%) |
SCD/SCA, sudden cardiac death/sudden cardiac arrest; ICD, implantable cardioverter-defibrillator.
Patient characteristics
| SCN5A-E1784K positive | SCN5A-E1784K negative | Total | |
|---|---|---|---|
| n | 16 | 7 | 23 |
| Female | 9 (56%) | 2 (29%) | 11 (48%) |
| Age at ajmaline challenge (years) | 26.0 ± 13.9 | 30.0 ± 15.9 | 27.2 ± 14.3 |
| Family history of SCD/SCA in first-degree relative | 6 (38%) | 3 (43%) | 9 (39%) |
| Symptoms (SCA or syncope) | 2 (13%) | 0 | 2 (9%) |
| ICD implanted | 8 (50%) | 0 | 8 (35%) |
| SCN5A-E1784K positive | SCN5A-E1784K negative | Total | |
|---|---|---|---|
| n | 16 | 7 | 23 |
| Female | 9 (56%) | 2 (29%) | 11 (48%) |
| Age at ajmaline challenge (years) | 26.0 ± 13.9 | 30.0 ± 15.9 | 27.2 ± 14.3 |
| Family history of SCD/SCA in first-degree relative | 6 (38%) | 3 (43%) | 9 (39%) |
| Symptoms (SCA or syncope) | 2 (13%) | 0 | 2 (9%) |
| ICD implanted | 8 (50%) | 0 | 8 (35%) |
SCD/SCA, sudden cardiac death/sudden cardiac arrest; ICD, implantable cardioverter-defibrillator.
Baseline electrocardiogram
No patient showed a spontaneous type 1 Brugada pattern at baseline, and one patient exhibited a type 2 pattern. The longest QTc at baseline was 505 ms. The rate-corrected QT and the rate-corrected JT (JTc) intervals were significantly longer in SCN5A-E1784K carriers (P < 0.001 and P = 0.03, respectively), and there was a trend towards a longer PR interval at baseline in mutation carriers vs. non-carriers. Complete electrocardiographic measurements are shown in Table 2.
Electrocardiogram measurements before and after ajmaline administration
| SCN5A-E1784K positive | SCN5A-E1784K negative | ||||||
|---|---|---|---|---|---|---|---|
| Baseline | Ajmaline | Pa | Baseline | Ajmaline | Pa | Pb | |
| RR interval | 855 ± 246 ms | 710 ± 146 ms | <0.001 | 830 ± 196 ms | 704 ± 80 ms | 0.086 | n.s. |
| PR interval | 174 ± 28 ms | 219 ± 27 ms | <0.001 | 152 ± 23 ms | 191 ± 22 ms | 0.001 | 0.079 |
| QRS interval | 96 ± 18 ms | 135 ± 28 ms | <0.001 | 88 ± 9 ms | 113 ± 12 ms | 0.001 | n.s. |
| QTc | 455 ± 29 ms | 475 ± 39 ms | 0.018 | 407 ± 20 ms | 453 ± 13 ms | 0.003 | 0.001 |
| JTc1 | 349 ± 42 ms | 314 ± 31 ms | 0.003 | 309 ± 28 ms | 317 ± 21 ms | n.s. | 0.031 |
| JTc2 | 350 ± 45 ms | 312 ± 23 ms | 0.004 | 308 ± 30 ms | 312 ± 16 ms | n.s. | 0.036 |
| Maximum J point elevation | 0.055 ± 0.059 mV | 0.251 ± 0.140 mV | <0.001 | 0.049 ± 0.072 mV | 0.113 ± 0.143 mV | n.s. | n.s. |
| SCN5A-E1784K positive | SCN5A-E1784K negative | ||||||
|---|---|---|---|---|---|---|---|
| Baseline | Ajmaline | Pa | Baseline | Ajmaline | Pa | Pb | |
| RR interval | 855 ± 246 ms | 710 ± 146 ms | <0.001 | 830 ± 196 ms | 704 ± 80 ms | 0.086 | n.s. |
| PR interval | 174 ± 28 ms | 219 ± 27 ms | <0.001 | 152 ± 23 ms | 191 ± 22 ms | 0.001 | 0.079 |
| QRS interval | 96 ± 18 ms | 135 ± 28 ms | <0.001 | 88 ± 9 ms | 113 ± 12 ms | 0.001 | n.s. |
| QTc | 455 ± 29 ms | 475 ± 39 ms | 0.018 | 407 ± 20 ms | 453 ± 13 ms | 0.003 | 0.001 |
| JTc1 | 349 ± 42 ms | 314 ± 31 ms | 0.003 | 309 ± 28 ms | 317 ± 21 ms | n.s. | 0.031 |
| JTc2 | 350 ± 45 ms | 312 ± 23 ms | 0.004 | 308 ± 30 ms | 312 ± 16 ms | n.s. | 0.036 |
| Maximum J point elevation | 0.055 ± 0.059 mV | 0.251 ± 0.140 mV | <0.001 | 0.049 ± 0.072 mV | 0.113 ± 0.143 mV | n.s. | n.s. |
QTc, rate-corrected QT interval; JTc1 and JTc2, rate-corrected JT interval (see the Methods section for correction formulas).
aFor baseline vs. ajmaline.
bFor baseline SCN5A-E1784K positive vs. baseline SCN5A-E1784K negative.
Electrocardiogram measurements before and after ajmaline administration
| SCN5A-E1784K positive | SCN5A-E1784K negative | ||||||
|---|---|---|---|---|---|---|---|
| Baseline | Ajmaline | Pa | Baseline | Ajmaline | Pa | Pb | |
| RR interval | 855 ± 246 ms | 710 ± 146 ms | <0.001 | 830 ± 196 ms | 704 ± 80 ms | 0.086 | n.s. |
| PR interval | 174 ± 28 ms | 219 ± 27 ms | <0.001 | 152 ± 23 ms | 191 ± 22 ms | 0.001 | 0.079 |
| QRS interval | 96 ± 18 ms | 135 ± 28 ms | <0.001 | 88 ± 9 ms | 113 ± 12 ms | 0.001 | n.s. |
| QTc | 455 ± 29 ms | 475 ± 39 ms | 0.018 | 407 ± 20 ms | 453 ± 13 ms | 0.003 | 0.001 |
| JTc1 | 349 ± 42 ms | 314 ± 31 ms | 0.003 | 309 ± 28 ms | 317 ± 21 ms | n.s. | 0.031 |
| JTc2 | 350 ± 45 ms | 312 ± 23 ms | 0.004 | 308 ± 30 ms | 312 ± 16 ms | n.s. | 0.036 |
| Maximum J point elevation | 0.055 ± 0.059 mV | 0.251 ± 0.140 mV | <0.001 | 0.049 ± 0.072 mV | 0.113 ± 0.143 mV | n.s. | n.s. |
| SCN5A-E1784K positive | SCN5A-E1784K negative | ||||||
|---|---|---|---|---|---|---|---|
| Baseline | Ajmaline | Pa | Baseline | Ajmaline | Pa | Pb | |
| RR interval | 855 ± 246 ms | 710 ± 146 ms | <0.001 | 830 ± 196 ms | 704 ± 80 ms | 0.086 | n.s. |
| PR interval | 174 ± 28 ms | 219 ± 27 ms | <0.001 | 152 ± 23 ms | 191 ± 22 ms | 0.001 | 0.079 |
| QRS interval | 96 ± 18 ms | 135 ± 28 ms | <0.001 | 88 ± 9 ms | 113 ± 12 ms | 0.001 | n.s. |
| QTc | 455 ± 29 ms | 475 ± 39 ms | 0.018 | 407 ± 20 ms | 453 ± 13 ms | 0.003 | 0.001 |
| JTc1 | 349 ± 42 ms | 314 ± 31 ms | 0.003 | 309 ± 28 ms | 317 ± 21 ms | n.s. | 0.031 |
| JTc2 | 350 ± 45 ms | 312 ± 23 ms | 0.004 | 308 ± 30 ms | 312 ± 16 ms | n.s. | 0.036 |
| Maximum J point elevation | 0.055 ± 0.059 mV | 0.251 ± 0.140 mV | <0.001 | 0.049 ± 0.072 mV | 0.113 ± 0.143 mV | n.s. | n.s. |
QTc, rate-corrected QT interval; JTc1 and JTc2, rate-corrected JT interval (see the Methods section for correction formulas).
aFor baseline vs. ajmaline.
bFor baseline SCN5A-E1784K positive vs. baseline SCN5A-E1784K negative.
Ajmaline challenge
Ajmaline challenge was positive in 12 out of 16 (75%) SCN5A-E1784K mutation carriers, but negative in all non-carriers (P = 0.001).
The PR interval was prolonged by ajmaline in all patients (167 ± 28 to 210 ± 28 ms, P < 0.001), as was QRS duration (93 ± 16 to 128 ± 26 ms, P < 0.001). Driven by a significant QRS widening, the QTc interval was significantly prolonged by ajmaline in mutation carriers as well as non-carriers. A significant shortening of JTc (JTc1 and JTc2 by 35 ± 40 and 38 ± 45 ms, respectively; P < 0.05 for both) was seen in mutation carriers, while no effect was observed in non-carriers. The effect of ajmaline on the JTc interval is shown in Figure 1.
JTc1 at baseline and after ajmaline. Red lines denote SCN5A-E1784K mutation carriers and turquoise lines non-carriers.
Comparing mutation carriers with a positive ajmaline challenge and those without, a trend towards longer baseline QTc was seen in those with a positive challenge, although it did not reach significance (460 ± 30 vs. 440 ± 23 ms, P = 0.23). Baseline JTc1 and JTc2 were significantly longer in mutation carriers with a positive ajmaline challenge compared with those with a negative one (361 ± 40 vs. 312 ± 16 ms and 363 ± 45 vs. 311 ± 10 ms, respectively; P < 0.05 for both). A representative ajmaline challenge of a mutation carrier is shown in Figure 2.
Safety of ajmaline challenge
Ajmaline was well tolerated by all subjects. No major adverse events were associated with the ajmaline challenge, especially no ventricular tachycardia or ventricular fibrillation and no higher-degree AV block. One patient developed multiple asymptomatic premature ventricular contractions (PVCs), concurrent with the appearance of a Brugada type 1 ECG. Ajmaline infusion was stopped and PVCs subsided within 3 min.
Discussion
In the present study, we report the largest cohort of SCN5A-E1784K carriers undergoing ajmaline challenge for the diagnosis of the potential overlap of LQT3 and BrS to date. While anecdotal reports of positive sodium blocker challenges exist,6,12,13 this is the first study to systematically perform ajmaline challenge in SCN5A-E1784K carriers. Sixteen mutation carriers from four unrelated families underwent ajmaline challenge, while seven mutation negative family members served as a control group.
The main findings of the current study are as follows:
75% of SCN5A-E1784K mutation carriers showed the Brugada phenotype following ajmaline challenge. All non-carriers had a negative ajmaline challenge.
SCN5A-E1784K mutation carriers with a negative ajmaline challenge seem to exhibit a less severe electrocardiographic phenotype with respect to prolongation of repolarization.
Ajmaline challenge was well tolerated in carriers of SCN5A-E1784K.
When expressed in vitro, the mutated channels exhibit an increased persistent sodium current, a fundamental biophysical property leading to a LQT3 phenotype.5,6 Additionally, the activation equilibrium in SCN5A-E1784K is shifted to less negative membrane potentials, leading to decreased sodium current during Phase 0 of the action potential, a hallmark feature of BrS.6 Clinically, SCN5A-E1784K mainly causes LQTS with a partial overlap of BrS and cardiac conduction disease. In one study by Makita et al., LQTS was diagnosed in nearly all mutation carriers (93%), while only 15% fulfilled diagnostic criteria for BrS. Sinus node disease was observed in 39% of mutation carriers.6
Baseline electrocardiogram
As expected for a gain of function mutation, which has initially been described as causing LQTS,5 the QTc interval was significantly prolonged in SCN5A-E1784K carriers. The rate-corrected QT interval prolongation is caused by prolonged repolarization (JT interval). QRS width was within normal limits in both groups at baseline condition.
None of our patients showed a spontaneous Brugada type 1 ECG. These findings are consistent with previous reports: Spontaneous diagnostic Brugada phenotype is rare in LQT3 patients. None of the three patients reported by Priori et al. and only 1 out of 41 mutation carriers in the series by Makita et al. demonstrated a diagnostic Brugada phenotype in the absence of sodium channel blockade.6,13
Electrocardiogram of a mutation carrier before (baseline) and after ajmaline administration. Note the Brugada type I ST segment elevation in lead V1 and V2 and the shortening of the JT interval following ajmaline.
Ajmaline challenge
To date, there are limited data on consequent sodium channel blocker challenges in patients with LQT3, especially caused by SCN5A-E1784K. Priori et al. reported sodium channel blocker challenges in 13 LQT3 patients, of which 3 were carriers of SCN5A-E1784K. One of these patients developed ST segment elevation diagnostic for BrS after administration of flecainide.13 Another patient carrying the mutation developed a type 1 Brugada ECG during pilsicainide challenge.12 In the larger series by Makita et al., nine patients underwent sodium channel blocker challenge. Drugs used were mexiletine, ajmaline, flecainide, and pilsicainide. The test was positive in five mutation carriers.6 Taking together all 13 sodium channel blocker challenges in SCN5A-E1784K carriers published to date, the overlap between LQTS and BrS is expected to be ∼50%.
In the present study, the proportion of positive sodium channel blocker challenges was higher than that in those previous reports. Ajmaline challenge has never been performed thoroughly in patients with SCN5A-E1784K. Thus, the overlap might be as high as presented in the current study. However, there are further differences compared with the published series: First, modified higher intercostal right precordial leads were probably not used in the studies by Makita and Priori.6,13 It has been shown that additional recordings in the third and second intercostal spaces increase sensitivity for a spontaneous Brugada pattern as well as for a positive sodium channel blocker challenge. Inter-individual differences in the exact location of the right ventricular outflow tract have been linked to differing body surface distributions of leads exhibiting the type 1 ECG.10 The routine use of modified higher intercostal right precordial leads is therefore recommended.7
The second difference is the sodium channel blocker administered to unmask the Brugada pattern. The previous studies used flecainide, mexiletine, or pilsicainide6,12,13 in contrast to ajmaline in the present study. It has been shown that ajmaline is more effective than flecainide in unmasking BrS.8
Taken together, the sodium channel blocker challenge protocol used in the present study probably carries a higher sensitivity for the detection of BrS than those used in previous studies.
Ajmaline effect on repolarization
Sodium channel blockers, such as mexiletine,14 flecainide,15 and ranolazine,16 have been used in patients with LQT3 to shorten the QT interval and are expected to reduce the risk for torsade de pointes. This effect is due to an inhibition of the late sodium current INa-L, which is responsible for QT prolongation in LQT3.1 Class I antiarrhythmic drugs do not only block INa-L but also the fast (‘transient’) sodium current INa-T responsible for Phase 0 upstroke of the cardiac action potential. The inhibitory effect on both currents is almost indiscriminate for flecainide.17 The inhibition of the fast sodium current increases an intrinsic imbalance between INa-T and the transient outward current Ito mainly in the right ventricular myocardium and aggravates the BrS phenotype observed.1
Thus, specific INa-L blockers present a promising therapeutic principle especially in LQT3/BrS overlap syndromes. The only INa-L blocker in clinical use, Ranolazine, exhibits selectivity for INa-L over INa-T with the inhibition of INa-L being up to 38-fold more potent.17 However, this selectivity was significantly reduced in two LQT3 mutations studied,18 raising concerns of safety in LQT3/BrS overlap syndromes. The novel substance eleclazine (formerly GS-6615) is reported to act more selectively on INa-L, but data are limited thus far.19
While the inhibition of INa-T by ajmaline has been well characterized, effects of ajmaline on INa-L have not been reported yet. Ajmaline significantly prolonged QRS in mutation carriers as well as non-carriers, thus leading to QTc prolongation in both groups. A possible ajmaline-induced shortening of repolarization in mutation carriers could therefore not be appreciated from the QTc intervals measured. In order to specifically evaluate the effect of ajmaline on repolarization, JTc was calculated. While no significant effect on JTc was seen in mutation negative subjects, we observed a significant shortening of more than 30 ms in mutation carriers. This suggests that the persistent late sodium current, which has been shown to be responsible for QT interval prolongation in SCN5A-E1784K,6 is ajmaline sensitive. For the first time, we could demonstrate that ajmaline shortens repolarization in patients with LQT3.
Differential response to ajmaline challenge
It remains speculative why the ajmaline challenge was negative in four SCN5A-E1784K mutation carriers. Baseline ECG characteristics correlating with the result of the ajmaline challenge in mutation carriers are difficult to evaluate due to the small number of negative challenges in our cohort. A difference in baseline QTc was not statistically significant. There was, however, a significantly shorter baseline JTc in mutation carriers with a negative ajmaline challenge. Even in a single subject with LQTS, QTc and JTc are highly variable in serial ECGs.20 The phenotype in patients with BrS also fluctuates between diagnostic and non-diagnostic ECGs over time.21 QT prolongation in LQT3 and the Brugada phenotype in BrS are both blunted by catecholaminergic stress.22 Therefore, it is plausible that differences in autonomic tone among subjects at the time of ajmaline challenge account at least partly for the observed differential response.
Additional genetic polymorphisms in the SCN5A gene might affect the penetrance of the actual mutation. A number of polymorphisms have been shown to aggravate or ameliorate the effect of LQT3- or BrS-causing mutations.23,24 Further studies are warranted to elucidate the effect of such modifiers on the clinical phenotype of SCN5A-E1784K.
Safety of ajmaline challenge in SCN5A-E1784K carriers
Sodium blocker challenge may induce sustained ventricular arrhythmias in patients with BrS. Early studies reported a considerable incidence of arrhythmic complications of sodium blocker challenge.25 Since then, changes to the protocol and strict adherence to termination criteria such as QRS widening and non-sustained arrhythmias have led to increased safety and reduced incidence of sustained ventricular arrhythmias. In the largest multicentre series of ajmaline challenges for the diagnosis of BrS, the rate of sustained ventricular arrhythmias was reported to be 0.15%.9,26 No large series of ajmaline challenges in LQT3 has been reported; thus, no safety data are available in this population. No adverse events occurred in our cohort. The present study together with the previous reports6,12,13 suggests that sodium channel blocker challenge can safely be performed in LQT3.
Limitations
The main limitation of the present study is the low number of subjects and controls. However, LQT3 is rare and even in multicentre co-operations, identification of larger cohorts is challenging. Another limitation is the lack of long-term follow-up: It is unknown whether patients with overlap differ in risk from those without.
Due to the multicentre nature of the study, the extent of genotyping varied between patients. Thus, possible associations between the response to ajmaline and additional modulating polymorphisms could not be analysed. Also, we included only patients with the specific SCN5A-E1784K mutation in our study. While the findings for this mutation are quite robust, the present data might not be pertinent to other mutations.
Clinical implications
The current expert consensus statement7 does not generally recommend the use of sodium channel blockers, including flecainide, mexiletine, and ranolazine, in LQT3, but mentions it on an observational trial basis.7 Recent data for mexiletine suggest that the drug not only shortens the QT interval in LQT3 patients but also prevents arrhythmic events.14 However, mexiletine is unavailable in several European countries, and clinicians might want to substitute it with other Class I antiarrhythmic drugs such as flecainide which is contraindicated in BrS. The Brugada syndrome overlap should therefore be excluded. Selective inhibitors of the late sodium current are a promising alternative, but the selectivity seems to differ in different SCN5A mutations.18
Although no outcome data exist and the clinical relevance of the Brugada pattern in these patients is therefore presently unknown, we do not recommend the initiation of Class I antiarrhythmic drugs in patients with overlap syndrome until further evidence regarding risk and benefit emerges. Besides that, risk stratification and treatment according to current guidelines for LQTS seem prudent. Patients should, however, additionally be counselled to avoid triggers known to be arrhythmogenic in BrS.
Conclusion
We have shown that the proportion of LQT3/BrS overlap in carriers of the most common LQT3 causing mutation is relevant. Therefore, ajmaline challenge represents an important diagnostic step to rule out potential BrS overlap in these patients before starting sodium channel blockers, which are otherwise beneficial in LQT3. Whether selective inhibitors of INa-L such as ranolazine or eleclazine could ameliorate LQT3 without the risk of aggravating concomitant BrS remains to be shown. As INa-L selectivity of ranolazine is reduced in some SCN5A mutations, caution is warranted and potential BrS overlap should be taken into account.
Conflict of interest: none declared.
